Soft proteins can enter the nucleus faster


To perform various functions, such as instructing the nucleus to turn particular genes on or off, proteins must enter and exit the nucleus, the cell's control center. These proteins pass through a channel called the “nuclear pore complex” which is located outside the nucleus.

Previously, studies have shown that the size and structure of these proteins affects their ability to cross-link. A new survey from scientists at the Francis Crick Institute and King's College London provides evidence that mechanical properties can influence the ability of a protein to enter the pore.

Scientists found that the softness or stiffness of proteins in certain regions can determine how fast or slow they enter the nucleus.

Scientists tracked the movement of proteins in single cells. They found that in proteins with similar size and composition of amino acids (their building blocks), the mechanical stability of the protein's nuclear-localization sequence (a particular sequence that allows the protein to enter the nucleus) influences how close it is. That's how fast or slow it can be to cross.

They found that proteins that had flexible regions adjacent to this sequence could enter the nucleus more quickly. Then, to facilitate easier entry of the protein into the nucleus, the scientists created a soft tag that could be inserted close to the sequence on the rigid protein. This was investigated by tagging MRTF, a transcription factor that helps cells move throughout the body and activate certain genes. Cell mobility was increased by adding a soft tag to MRTF, allowing it to enter the nucleus more rapidly.

The scientists then designed a soft tag that could be added near the sequence on the hard proteins to help them enter the nucleus more easily.

This was investigated by tagging MRTF, a transcription factor that helps cells move throughout the body and activate specific genes. Adding a soft tag to the MRTF increased the mobility of the cell, allowing it to enter the nucleus more quickly. Scientists believe it could be a helpful tool for rapidly delivering drugs to the nucleus or labeling transcription factors to boost the activity of specific genes.

Sergi García-Menayes, group leader of the Single Molecule Mechanobiology Laboratory at the Francis Crick Institute and professor of biophysics at King's College London, said: “We have made a fundamental discovery that the mechanics of a protein – how soft or stiff it is in the region that leads to translocation – controls its entry into the nucleus of the cell.”

“Although we only looked at the nuclear pore, this mechanism may regulate entry into other parts of the cell, such as mitochondria or proteasomes. Knowing that more flexible proteins can enter the nucleus faster could help us design more targeted drugs.

Rafael Tapia-Rojo, co-first author, a former postdoc at Crick and now a lecturer in biological physics at King's College London, said: “Our findings were unexpected, and it was surprising to see that measurements at the single molecule level using a newly designed optomechanical approach could be directly linked to what happens at the cellular level.”

Journal Reference:

  1. Panagaki, F. and others, (2024). Structural anisotropy results in mechanical-directional transport of proteins into nuclear pores. nature physics, DOI: 10.1038/s41567-024-02438-8




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